Suspension of loteprednol etabonate for ear, eye, or nose treatment

ABSTRACT

The invention provides novel compositions of matter for delivering water-insoluble steroid drugs suitable for therapeutic use. The invention also provides stable aqueous suspensions of water-insoluble steroid drugs of particle sizes of ≦30 μm which remain in such a state so as to allow for immediate suspension, when desired, even after extended periods of settling.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of application Ser. No.08/142,743 filed Oct. 25, 1993, now U.S. Pat. No. 5,540,930.

FIELD OF INVENTION

The invention relates to aqueous suspensions for treatment of ophthalmicand otolaryngological inflammations.

BACKGROUND OF THE INVENTION

Numerous drugs are prepared in the form of suspensions for ophthalmic,oral, otic, nasal respiratory is topical, and parenteral applications.Formulation of pharmaceutical dosages of water-insoluble drugs assuspensions is frequently hampered by the subsequent formation of cakesresulting from aggregation of the suspended material. Polymericcompounds (e.g. polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA),dextran) are commonly used to stabilize such suspensions. An alternativeapproach to the preparation of such drugs is to enhance the solubilityof the drugs within the formulation by vehicles including emulsions,liposomes, and cyclodextrins. However, certain drugs, in theirtherapeutic concentrations, are not sufficiently stabilized orsolubilized by these methods for the above-mentioned applications.

Topical steroids such as corticosteroids are commonly used foranti-inflammatory therapy of the eye, especially for treatinginflammatory conditions of the palpebral or bulbar conjunctiva, corneaand anterior segment of the globe. Common therapeutic applications forsteroids include allergic conjunctivitis, acne rosacea, superficialpunctate keratitis and iritis cyclitis. Steroids also are used toameliorate inflammation associated with corneal injury due to chemicalor thermal burns, or penetration of foreign bodies. Such conditions mayresult from surgery, injury, allergy or infection to the eye and cancause severe discomfort.

Despite their therapeutic advantages, topical ocular use ofcorticosteroids is associated with a number of complications, includingposterior subcapsular cataract formation, elevation of intraocularpressure, secondary ocular infection, retardation of corneal woundhealing, uveitis, mydriasis, transient ocular discomfort and ptosis.Numerous systemic complications also may arise from the topical ocularapplication of corticosteroids. These complications include adrenalinsufficiency, Cushing's syndrome, peptic ulceration, osteoporosis,hypertension, muscle weakness or atrophy, inhibition of growth,diabetes, activation of infection, mood changes and delayed woundhealing.

Topical steroids for treating ocular inflammations can be based on softdrugs. Soft drugs, as is known in the art, are designed to providemaximal therapeutic effect and minimal side effects. By one approach,synthesis of a "soft drug" can be achieved by structurally modifying aknown inactive metabolite of a known active drug to produce an activemetabolite that undergoes a predictable one-step transformation in-vivoback to the parent, (see, U.S. Pat. Nos. 4,996,335 and 4,710,495 forsoft steroids) inactive metabolite. "Soft drugs" therefore arebiologically active chemical components characterized by predictable invivo metabolism to non-toxic derivatives after they provide theirtherapeutic effect.

Pharmaceutical compositions of water-insoluble drugs such ascorticosteroids in aqueous suspensions for ocular and other uses mustsatisfy constraints imposed by physiological compatibilities such as pH,osmolality, and article size of the suspended steroids. Furthermore,these compositions must meet requirements for reservative efficiency andease of suspension over extended periods of time.

Therapeutic suspensions of corticosteroids typically employ polymericcompounds such as polyvinyl pyrrolidone ("PVP") and polyvinyl alcohol("PVA") as suspending agents in concentrations ranging from 0.1 to 10%(U.S. Pat. No. 2,861,920). Combinations of polymeric compounds such asPVP, PVA, sodium carboxymethylcellulose ("CMC"), and dextran, withsurface-active agents such as Polysorbate 80, Polysorbate 20, andtyloxapol also have been used to stabilize corticosteroid suspensionsintended for ophthalmic, nasal, and otic uses.

The amounts of polymeric compounds and surface active agents must bedetermined to provide stability to suspensions of corticosteroids.Excessive amounts of polymeric compounds may hamper the antimicrobialeffects of preservatives added to the suspension. Also, pharmaceuticalocular and nasal dosages of these suspensions either must be buffered orhave an appropriate pH with no buffering capacity. These suspensionsalso should be isotonic.

Loteprednol etabonate ("LE") is a known soft corticosteroid based on theknown inactive metabolite prednisolone acetate of the active drugprednisolone. See U.S. Pat. Nos. 4,996,335 and 4,710,495.

LE is an analog of prednisolone that does not have a 20-keto groupattached to the 17β-position. Instead, the 17-β position is occupiedwith a metabolically-labile ester function. In biological systems, LE ishydrolysed to the inactive carboxylic acid metabolite (PJ-91) that doesnot bind to glucocorticoid receptors. LE also provides superior safetyby reducing the risk of steroid induced cataracts and elevation ofintra-ocular pressure. The lability of LE to enzymes located in theblood and/or liver also reduces the likelihood of systemic side effects.LE therefore provides therapeutic advantages over other corticosteroidsby providing efficacy similar to its parent compound, namely,prednisolone acetate, with fewer deleterious systemic side effects. Softsteroids have the potential advantage of treating inflammation withoutinducing elevation of intraocular pressure. In addition, soft steroidscan provide the added benefit of a lower tendency to induce cataractswhich may result from interaction of corticosteroids with the ocularlens proteins.

Formulation of stable aqueous suspensions of LE for ocular applicationsand other uses, however, has been hampered by agglomeration of thesteroid particles. Unexpectedly, common tonicity agents such as aqueoussolutions containing 0.9% NaCl, 0.1% EDTA, or phosphate buffer, even inconcentrations as low as 1 mM, can not be employed to provide stableaqueous suspensions of corticosteroids such as LE.

A need therefore exists for aqueous suspensions of corticosteroids suchas LE which can be formulated without agglomeration. A further needexists for aqueous suspensions which have therapeutically effectiveamounts of corticosteroids such as LE but which avoid the problemsassociated with the steroid suspensions of the prior art.

SUMMARY OF THE INVENTION

The invention provides novel compositions of matter containingwater-insoluble drugs suitable for therapeutic use. The inventionprovides stable aqueous suspensions of water-insoluble drugs of meanparticle sizes of ≦15 μm which remain in such a state so as to allow forimmediate suspension, when desired, even after extended periods ofsettling.

More particularly, the invention is directed to aqueous suspensions ofsoft corticosteroids such as loteprednol etabonate suitable fortherapeutic use in the eye, ear, or nose. The aqueous suspensions of LEare surprisingly stable and can remain in a state suitable for immediatesuspension when desired, even after extended periods of settling. Thesuspensions of the invention, moreover, do not cause discomfort uponapplication.

Alternatively, the present invention is directed to aqueous formulations(e.g., suspensions or solutions) wherein the amount of corticosteroidsis either minimized (e.g., suspensions) or altogether avoided (e.g.,solutions) for the therapeutic use in the eye, ear, nose or throat forthe topical treatment of inflammatory conditions therein.

The aqueous suspensions of the invention containing a steroid comprisecomponent (A) of a therapeutic quantity of a "soft" steroid such as LEpresent as particles preferably having a mean diameter of less thanabout fifteen microns, component (B) of a suspending agent of a nonionicpolymer in an aqueous medium, and component (C) of a nonionic surfaceactive agent. Advantageous molar ratios of (A):(B):(C) can vary fromabout 1:0.01:0.05 to 1:20:1.

The steroid of component (A) preferably is loteprednol etabonate and isadded to obtain a final concentration in the suspension of 0 to about 2%by weight, more preferably about 0.01-1% by weight and most preferablyabout 0.05-0.5% by weight. The suspending agent may be any nonionicpolymer which is soluble in an aqueous medium, and can be present in anamount of about 0.2 to 2% by weight, preferably about 0.3 to 1.75% byweight, more preferably about 0.4-1.5% by weight. The molar ratio ofcomponent (A) to component (B) typically is in the range of about 1:0.01to about 1:20, preferably about 1:0.05 to about 1:10 and more preferablyabout 1:0.1 to 1:3.

The nonionic surfactant of component (C) of the composition may be anyone of a wide variety of nonionic alkylene oxide condensates of anorganic compounds which contain one or more hydroxyl groups. Thiscomponent (C) is advantageously present in an amount of between about0.05 and 1% by weight of the composition. The molar ratio of component(A) to component (C) typically is in the range of about 1:0.05 to about1:1.

The compositions generally include component (D) of a nonionic tonicityagent for producing isotonicity, and, if necessary, component (E) of oneor more preservatives.

It is essential that these components (A)-(D) be nonionic insofar aspossible since it has now been discovered that the presence of ions isthe major cause of caking. Thus, the preferred tonicity agents would benonionic diols such as glycerol or mannitol rather than the commonlyused sodium chloride. The nonionic tonicity agent is preferably presentin an amount of about 0.5 to 10% by weight, more preferably about 1 to7%, and most preferably about 1.5 to 4%.

Accepted preservatives such as benzalkonium chloride and disodiumedetate (EDTA) may be included in the suspensions of the invention inconcentrations sufficient for effective antibacterial action, preferablyabout 0.0001 to 0.025%, based on the weight of the suspension.

Having briefly summarized the invention, the invention will now bedescribed in detail by reference to the following specification andnon-limiting examples. Unless otherwise specified, all percentages areby weight.

DETAILED DESCRIPTION OF THE INVENTION

Therapeutic suspensions of LE for ophthalmic or otolaryngological usesare made by aseptic preparation. Purity levels of all materials employedin the suspensions of the invention exceed 98%. The suspensions of theinvention are prepared by thoroughly mixing the drug (component (A)),suspending agent (component (B)), and surface active agent (component(C)). Optionally, tonicity agents (component (D)) and preservatives(component (E)) may be included.

Drugs of component (A), when used, are preferably soft steroids and mostpreferably LE. Also, other steroids such as beclomethasone,betamethasone, fluocinolone, fluorometholone, exednisolone, may beemployed. The suspensions of component (A) of the invention have aparticle size of about 0.1-30 μm, preferably about 1-20 μm, mostpreferably about 2-10 μm in mean diameter. LE in this size range iscommercially available from suppliers such as the Sipsy Co. (Avrille,France).

The nonionic polymer of component (B) can be any nonionic water-solublepolymer. Typical compounds such as PVP, PVA, dextran or cyclodextrin canbe used in a concentration of about 0.2-2% by weight, and preferablyabout 0.3-1.75% by weight.

Component (C) is a surface-active agent that is acceptable forophthalmic or otolaryngological uses. Preferably, this surfactant isnon-ionic. Generally, the nonionic surfactant is a nonionic alkyleneoxide condensate of an organic compound which contains one or morehydroxyl groups. For example, ethoxylated and/or propoxylated alcohol orester compounds or mixtures thereof are commonly available and are wellknown to those skilled in the art. Useful surface active agents includebut are not limited to POLYSORBATE 80, tyloxapol, TWEEN 80 (e.g.,polyoxyethylene sorbitan mono-oleate ester;ICI America Inc., Wilmington,Del.), PLURONIC F-68 (from BASF, Ludwigshafen, Germany) and thePOLOXAMER (e.g., poly(oxypropylene)-poly(oxyethylene) copolymer)surfactants can also be used. See, Remington's Pharmaceutical Sciences,16th Edition, Arthur osol, Editor, Mack Publishing Company, Easton, Pa.(1980). See also, The United States Pharmacopeia, 21st Revision, TheNational Formulary, 16th Edition, United States PharmacopeialConvention, Inc., Rockville, Md., (Jan. 1, 1985). The tyloxapol andTWEEN surfactants are preferred because they are FDA approved for humanuse. The concentration in which the surface active agent may be used isonly limited by neutralization of the bacteriocidal effects on theaccompanying preservatives, or by concentrations which may causeirritation. Advantageously, the concentration of component (C) is about0.05 to 1% based on the weight of the suspension (or solution), andpreferably about 0.1 to 0.6%.

The tonicity agents of component (D) can be nonionic diols includingmannitol and preferably glycerol, in sufficient amounts to achieveisotonicity. The nonionic tonicity agent is advantageously present in anamount of about 1 to 7% by weight, and preferably about 1.5 to 4%.

The nonionic polymeric compounds of component (B), and the surfaceactive agents of component (C) have good solubility in water, havesufficient number of hydroxyl groups to interact with the steroid, andhave mild effects on the viscosity of the suspension. Final viscosityshould not exceed 80-centipoise.

In a preferred aspect, stable aqueous suspensions of LE are provided bypreparing aqueous suspensions of LE in concentrations of about 0.05-0.2%with about 0.3-1.5% PVP, about 2-3% glycerol, and about 0.05-1%tyloxapol.

The suspensions of the invention also may include additional therapeuticdrugs such as drugs for treating glaucoma, anti-inflammatory drugs,antibiotic drugs, anti-cancer drugs, anti-fungal drugs and anti-viraldrugs. Examples of anti-glaucoma drugs include but are not limited totimolol-base, betaxolol, atenolol, levobunolol, epinephrin, dipivalyl,oxonolol, acetazolamide-base and methazolamide. Examples ofanti-inflammatory drugs include but are not limited to non-steroids suchas piroxicam, indomethacin, naproxen, phenylbutazone, ibuprofen anddiclofenac. Additional therapeutic materials which may be employedinclude but are not limited to tobramycin, gentamycin or otherantibiotics.

Health regulations in various countries generally require thatophthalmic preparations shall include a preservative. Many well knownpreservatives that have been used in ophthalmic preparations of theprior art, however, cannot be used in the preparations of the invention,since those preservatives may no longer be considered safe for ocularuse, or may interact with the surfactant employed in the suspension toform a complex that reduces the bacteriocidic activity of thepreservative.

The preservatives of component (E) employed in the suspensions of theinvention therefore are chosen to not interact with the surface activeagent to an extent that the preservatives are prevented from protectingthe suspension from microbiological contamination. In a preferredembodiment benzalkonium chloride may be employed as a safe preservative,most preferably benzalkonium chloride with EDTA. Disodium edetate hasalso been found to be effective in reducing microbial growth in thepresent formulations. Other possible preservatives include but are notlimited to benzyl alcohol, methyl parabens, propyl parabens, thimerosal,chlorbutanol and benzethonium chlorides. Preferably, a preservative (orcombination of preservatives) that will impart standard antimicrobialactivity to the suspension and protect against oxidation of components(A)-(D) is employed. These preservatives are generally used in an amountof about 0.0001 to 0.025% by weight and preferably 0.001 to 0.015%.

Stable aqueous suspensions of the invention can be produced over a broadrange of pH values. A pH of about 4.5-7.4 especially is useful forpreparing the stable LE suspensions of the invention.

It has been surprisingly discovered that the carriers (i.e., components(B), (C), (D) and, optionally, (E)) for component (A) haveanti-inflammatory properties of their own. Thus, a solution ofcomponents (B), (C), (D) and, optionally, (E), at least partiallyrelieves inflammation when applied to inflamed ophthalmic orotolaryngological tissue. Thus, for example, when applied to the eye, inthe absence of a corticosteroid, a solution of components (B), (C) and(D) surprisingly produces at least a partial reduction of theinflammation of the eye. The addition of component (E) does not detractfrom this result.

Formulations in the form of a solution, when component (A) is absent,are prepared according to the procedures outlined for Examples 1-37,infra, with the exception that the concentration of component (B) ischanged to preferably between about 0.3-1.75% by weight and morepreferably between about 0.4-1.5% by weight. Components (C), (D) and (E)can be used in the same amounts as stated above.

For formulations in the form of a suspension, the aforementionedconcentration(s) of component (B) (see preceding paragraph) can be usedin combination with the concentration of component (A) as indicatedbelow. The concentration of component (A) is typically between about0.01-2% by weight, preferably between about 0.03-1% by weight, morepreferably between about 0.05-0.5% by weight and most preferably betweenabout 0.05-0.2% by weight. Such suspensions are prepared according tothe procedures outlined for Examples 1-37, infra, with the exceptionthat the concentration of components (A) and (B) is changed as indicatedherein. Components (C), (D) and (E) can be used in the same amounts asstated above.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodimentstherefore are to be construed as merely illustrative, and not limitativeof the remainder of the disclosure in any way whatsoever. In thefollowing examples, all parts and percentages are by weight unlessotherwise indicated,

EXAMPLES 1-37

Each of Examples 1-37 are prepared by dissolving the suspending agent(Component B) in water by gentle mechanical mixing. Subsequently, thesurfactant (Component C), the tonicity agent(s) and the preservatives(Components (D) and (E), respectively) are added in that order. Thesolution is then sterilized by filtration or autoclaving. LE,presterilized by irradiation, is added aseptically to the solution, andthe dispersion is then mixed at 12,000 rpm for one minute. The amountsof these components are shown in Table 1.

SIZE DETERMINATION

The size distributions of the LE particles in the samples of Table 1 aremeasured with a Coulter^(R) LS 130 instrument. An acceptable averageparticle size for ophthalmic suspensions is ≦15 μm. The results appearin Table 2.

                                      TABLE 1                                     __________________________________________________________________________    Example                                                                            SAMPLE COMPOSITION (% w/w)                                               Number                                                                             LE                                                                              Tween 80                                                                           Tyloxapol                                                                          Poloxamer-188                                                                        HPMC.sup.1                                                                        PVA                                                                              PVP                                                                              dextran                                                                           Osmolarity Agent                                                                      EDTA.sup.4                                                                        BKA.sup.5                   __________________________________________________________________________     1   0.5                                                                             --   0.2  --     --  0.6                                                                              -- --  --      --  --                           2   0.5                                                                             0.2  --   --     --  -- 0.2                                                                              --  10 mM PBS.sup.2                                                                       --  --                           3   0.5                                                                             --   0.4  --     0.2 -- 0.4                                                                              --  --      --  --                           4   0.5                                                                             --   0.2  --     --  0.2                                                                              -- --  10 mM PBS                                                                             --  --                           5   0.5                                                                             0.6  --   --     0.4 -- -- --  100 mM PBS                                                                            --  --                           6   0.5                                                                             0.4  --   --     --  1.4                                                                              -- --  5 mM PBS                                                                              --  0.001                        7   1 --   0.2  --     --  -- 1  --  --      --  --                           8   1 --   0.6  --     --  -- 1.4                                                                              --  --      --  --                           9   1 0.6  --   --     --  -- 1.4                                                                              --  --      --  --                          10   0.5                                                                             --   0.4  --     --  1  -- --  0.9% saline.sup.3                                                                     --  0.001                       11   0.5                                                                             0.4  --   --     --  1  -- --  0.9% saline                                                                           --  0.001                       12   0.5                                                                             0.6  --   --     --  -- 2  --  2.4% glycerol                                                                         0.01                                                                              0.01                        13   0.5                                                                             --   0.3  --     --  -- 1.5                                                                              --  2.4% glycerol                                                                         0.01                                                                              0.01                        14   0.5                                                                             --   0.3  --     --  -- 0.6                                                                              0.5 2.4% glycerol                                                                         0.01                                                                              0.015                       15   0.5                                                                             0.4  --   --     --  1.4                                                                              -- --  2.4% glycerol                                                                         --  0.001                       16   1 --   0.2  --     --  -- 1  --  2.4% glycerol                                                                         --  0.01                        17   0.5                                                                             --   0.6  --     --  1.4                                                                              -- --  2.4% glycerol                                                                         --  0.01                        18   0.5                                                                             --   --   0.6    --  -- 2  --  2.4% glycerol                                                                         0.01                                                                              0.004                       19   0.5                                                                             0.4  --   --     --  -- -- 1.6 2.4% glycerol                                                                         0.01                                                                              0.004                       20   0.5                                                                             --   0.4  --     --  -- -- 2.4 2.4% glycerol                                                                         0.01                                                                              0.01                        21   0.5                                                                             --   0.3  --     --  -- 1  --  2.4% glycerol                                                                         0.01                                                                              0.01                        22   0.5                                                                             0.6  --   --     --  1.4                                                                              -- --  2.4% glycerol                                                                         --  --                          23   0.5                                                                             0.6  --   --     --  1.4                                                                              -- --  2.4% glycerol                                                                         --  0.004                       24   0.5                                                                             0.6  --   --     --  -- -- 2   2.4% glycerol                                                                         0.01                                                                              0.01                        25   0.5                                                                             --   0.3  --     --  -- 0.6                                                                              --  2.4% glycerol                                                                         0.01                                                                              0.01                        26   0.5                                                                             --   0.3  --     --  -- 0.6                                                                              0.5 2.4% glycerol                                                                         0.01                                                                              0.01                        27   1 --   0.3  --     --  -- 0.6                                                                              0.5 2.4% glycerol                                                                         0.01                                                                              0.015                       28   1 --   0.3  --     --  -- 0.6                                                                              --  2.4% glycerol                                                                         0.01                                                                              0.015                       29   1 --   0.1  --     --  -- 0.4                                                                              --  2.4% glycerol                                                                         0.01                                                                              0.01                        30   0.5                                                                             --   0.2  --     --  -- 0.6                                                                              --  2.4% glycerol                                                                         0.01                                                                              0.01                        31   1 --   0.2  --     --  -- 0.6                                                                              --  2.4% glycerol                                                                         0.01                                                                              0.01                        32   1 --   0.2  --     --  -- 0.8                                                                              --  2.4% glycerol                                                                         0.01                                                                              0.015                       33   0.5                                                                             --   0.3  --     --  -- 1.5                                                                              --  2.4% glycerol                                                                         0.01                                                                              0.015                       34   1 --   0.4  --     --  -- 0.4                                                                              --  2.4% glycerol                                                                         0.01                                                                              0.01                        35   0.5                                                                             --   0.3  --     --  -- 0.6                                                                              0.3 2.4% glycerol                                                                         0.01                                                                              0.01                        36   0.5                                                                             --   0.1  --     --  -- 0.4                                                                              0.3 2.4% glycerol                                                                         0.01                                                                              0.01                        37   0.5                                                                             --   0.3  --     --  -- 0.6                                                                              --  2.4% glycerol                                                                         0.01                                                                              0.015                       __________________________________________________________________________     .sup.1 hydroxypropylmethyl cellulose                                          .sup.2 phosphate buffered physiological saline                                .sup.3 sodium chloride                                                        .sup.4 ethylene diamine tetraacetic acid                                      .sup.5 benzalkonium chloride                                             

                  TABLE 2                                                         ______________________________________                                        Example   Particle Size(s) (μm) and Fraction of Total Population           Number    Population A                                                                             A%       Population B                                                                           B%                                     ______________________________________                                        1         3.906+/-2.677                                                                            86.62    53.67+/-13.13                                                                          13.38                                  2         112.7+/-13.27                                                                            100      --       --                                     3         3.526+/-1.706                                                                            100      --       --                                     4         111.4+/-18.59                                                                            100      --       --                                     5         23.52+/-20.58                                                                            100      --       --                                     6         32.83+/-2.563                                                                            48.74    94.06+/-40.57                                                                          51.26                                  7         4.596+/-2.698                                                                            92.43    57.91+/-18.14                                                                          7.57                                   8         3.805+/-2.417                                                                            93.14    62.38+/-20.38                                                                          6.86                                   9         6.591+/-3.566                                                                            100      --       --                                     10        3.828+/-2.693                                                                            17.52    96.28+/-38.13                                                                          82.48                                  11        3.888+/-2.69                                                                             14.02    110.1+/-58.02                                                                          85.98                                  12        3.559+/-1.469                                                                            5.62     82.84+/-13.08                                                                          94.38                                  13        2.932+/-2.32                                                                             3.52     100.1+/-24,56                                                                          96.48                                  14        88.52+/-30.19                                                                            100      --       --                                     15        3.652+/-2.692                                                                            100      --       --                                     16        3.851+/-2.401                                                                            100      --       --                                     17        3.969+/-2.572                                                                            100      --       --                                     18        4.926+/-2.955                                                                            92.29    41.59+/-7.125                                                                          7.71                                   19        4.429+/-2,732                                                                            100      --       --                                     20        3.980+/-2.566                                                                            100      --       --                                     21        3.633+/-2.457                                                                            100      --       --                                     22        4.716+/-2.762                                                                            100      --       --                                     23        4.789+/-2.823                                                                            100      --       --                                     24        4.528+/-2.552                                                                            100      --       --                                     25        5.261+/-2.990                                                                            100      --       --                                     26        5.262+/-3.013                                                                            100      --       --                                     27        5.204+/-2.985                                                                            100      --       --                                     28        4.918+/-2.832                                                                            100      --       --                                     29        4.126+/-2.390                                                                            100      --       --                                     30        12.45+/-10.91                                                                            100      --       --                                     31        3.976+/-2.245                                                                            100      --       --                                     32        3.789+/-1.609                                                                            100      --       --                                     33        3.821+/-2.181                                                                            46.77    107.3+/-14.74                                                                          53.23                                  34        3.813+/-2.305                                                                            100      --       --                                     35        3.385+/-1.506                                                                            78.44    25.16+/-1.421                                                                          21.56                                  36        3.737+/-2.044                                                                            100      --       --                                     37        3.965+/-2.229                                                                            100      --       --                                     ______________________________________                                         1. In the Coulter particle size analysis two distinct populations of          particles were sometimes discerned. In these cases the two populations ar     denoted as populations A and B. If only a single population was detected      it is denoted population A.                                              

EVALUATION OF SUSPENDABILITY OVER TIME

Samples containing particles with desirable size distributions (averageof 2-10 um) are tested for stability using accelerated stability testsas well as "real time" studies.

Accelerated stability studies are performed by subjecting the samples toa centrifugal force of 5000×G for two minutes. The suspendability of thesettled material is tested by measuring the number of seconds of wristshaking required to eliminate visible residue attached to the container.Since existing marketed products require as much as sixty seconds ofwrist shaking to suspend the entire amount of settled residue, tenseconds is determined to be an acceptable amount of time to suspend theresidue. The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        RESUSPENSION OF LE SUSPENSIONS WHICH HAVE                                     UNDERGONE ACCELERATED AND NATURAL.sup.1  SETTLING                                                  Suspension of naturally                                                       settled material.sup.1                                   Example                                                                              Accelerated Stability         Months                                   Number (time to resuspend).sup.2                                                                   Initial Value (# inversions)                                                                  Tested.sup.3                             ______________________________________                                        15     15            --              10 (I)                                   16     5             --              10 (I)                                   17     5             --              10 (I)                                   18     5             --              9                                        19     5             --              9                                        20     --            67              9                                        21     --            46              9                                        22     --            83              9                                        23     --            37              9                                        24     --            --              6 (I)                                    25     5             27              8                                        26     5             22              6 (I)                                    27     5             35              6 (I)                                    28     5             35              8 (I)                                    29     --            49              7                                        30     5             25              7                                        31     5             43              7                                        32     --            74              7                                        33     --            136             3 (I)                                    34     --            40              7                                        35     --            18              7                                        36     --            48              7                                        37     --            46              8                                        ______________________________________                                         .sup.1 Refers to settling, at room temperature, on an open shelf              .sup.2 Number of seconds of wrist shaking to suspend material that was        settled by application of 5000 × G for 2 minutes.                       .sup.3 During the test period, samples were periodically examined to          verify the retention of the initial valules "I" indicates instability for     the noted period, i.e., agglomeration.                                   

The results shown in Table 3 show samples which do not form agglomeratesduring the longest period of observation. Acceptable samples require≦100 gentle inversions following the indicated period of settling.

The stability of suspensions intended for multiple doses is supported bythe addition of preservatives which prevent potential microbiologicalgrowth. The indicated preparations are prepared under aseptic conditionsand aliquots of each material are exposed to the indicatedmicrobiological organisms for four weeks and evaluated for growth asdescribed in the U.S. Pharmacopeia. The results, shown in Table 4,indicate whether the preservative was effective (+) or ineffective (-)according to U.S.P. requirements.

UNIDOSE SUSPENSIONS WITHOUT PRESERVATIVES

Compositions with satisfactory particle sizes and stabilities forunidose suspensions without preservatives appear in Table 5. Thesecompositions are satisfactory for ophthalmic or otolaryngological useswhen prepared under aseptic conditions and packaged in containers forsingle doses.

                  TABLE 4                                                         ______________________________________                                               Challenge Microorganism                                                       Staph.             Candida Asper.                                      Example                                                                              aureus    P. aerug.                                                                              albicans                                                                              niger E. coli                               ______________________________________                                        23     +         -        -       -     ND                                    24     +         -        -       -     ND                                    25     +         -        -       +     ND                                    26     +         +        +       +     ND                                    27     +         +        -       +     +                                     28     +         +        +       +     +                                     29     +         +        +       +     ND                                    30     +         +        +       +     +                                     31     +         +        +       +     +                                     32     +         +        +       +     +                                     ______________________________________                                         ND: denotes not done; (+) denotes challenge withstood; (-) denotes            unacceptable microbe growth                                                   The test was performed according to U.S.P. specifications.               

                                      TABLE 5                                     __________________________________________________________________________    COMPOSITIONS OF EXEMPLARY LE FORMULATIONS FOR UNIDOSE APPLICATION             Ex. No.                                                                           LE                                                                              Tween 80                                                                           Tyloxapol                                                                          Poloxamer-188                                                                        PVA                                                                              PVP                                                                              dextrin                                                                           glycerol                                                                          Purified Water                           __________________________________________________________________________     1  1 0.6  --   --     -- 1.4                                                                              --  2.4 Remainder                                 2  0.5                                                                             --   --   0.6    -- 2  --  2.4 Remainder                                 3  0.5                                                                             0.4  --   --     -- -- 1.6 2.4 Remainder                                 4  0.5                                                                             --   0.4  --     -- -- 2.4 2.4 Remainder                                 5  0.5                                                                             --   0.3  --     -- 1  --  2.4 Remainder                                 6  0.5                                                                             --   0.6  --     0.8                                                                              -- --  2.4 Remainder                                 7  0.5                                                                             0.6  --   --     1.4                                                                              0.8                                                                              --  2.4 Remainder                                 8  0.5                                                                             0.6  --   --     -- -- 2   2.4 Remainder                                 9  0.5                                                                             0.6  --   --     -- -- 2.4 2.4 Remainder                                10  0.5                                                                             --   0.3  --     -- 0.6                                                                              --  2.4 Remainder                                11  0.5                                                                             --   0.3  --     -- 0.6                                                                              0.5 2.4 Remainder                                12  1 --   0.3  --     -- 0.6                                                                              0.5 2.4 Remainder                                13  1 --   0.3  --     -- 0.6                                                                              --  2.4 Remainder                                14  1 --   0.1  --     -- 0.4                                                                              --  2.4 Remainder                                15  0.5                                                                             --   0.2  --     -- 0.6                                                                              --  2.4 Remainder                                16  1 --   0.2  --     -- 0.6                                                                              --  2.4 Remainder                                17  1 --   0.4  --     -- 0.6                                                                              --  2.4 Remainder                                18  1 --   0.2  --     -- 0.8                                                                              --  2.4 Remainder                                19  1 --   0.4  --     -- 0.4                                                                              --  2.4 Remainder                                20  0.5                                                                             --   0.4  --     -- 0.4                                                                              --  2.4 Remainder                                21  0.5                                                                             --   0.3  --     -- 0.6                                                                              0.3 2.4 Remainder                                22  0.5                                                                             --   0.1  --     -- 0.4                                                                              0.3 2.4 Remainder                                __________________________________________________________________________

EXAMPLE 38

The soft steroid loteprednol etabonate was formulated as an aqueousophthalmic suspension containing polyvinyl pyrrolidone (0.6%), glycerine(2.4%), tyloxapol (0.3%), edetate disodium (0.01%) and benzalkoniumchloride (0.01%). Loteprednol etabonate (0.5%) was incorporated intothis vehicle for use in clinical studies. During these studies, theformulation was evaluated on a total of 446 patients, 220 of which hadgiant papillary conjunctivitis ("GPC"), 145 of which had seasonalallergic conjunctivitis ("SAC") and 81 had acute anterior uveitis.

Loteprednol etabonate in this formulation was readily suspendablethroughout extended periods of storage (i.e., greater than 18 months) aswell as throughout the clinical treatment. The preparation was welltolerated in all patients and was significantly more effective than thevehicle itself, which was used as a placebo, with regard to thereduction of signs and symptoms of ocular inflammation.

The vehicle was administered as a placebo to 219 GPC patients and 143SAC patients. In SAC, treatment was initiated prophylactically, andtherefore it was not possible to quantitate accurately the placeboeffect. The GPC patients were enrolled in the study after the appearanceof signs or symptoms. A significant number of GPC patients experiencedclinically meaningful relief of signs and symptoms with the applicationof the vehicle alone. While the use of a demulcent solution applied fourtimes per day should have some benefit in the treatment of GPC, theextent to which this occurred was higher than expected. Specifically,the size of the papillae was reduced in 50% of the patients, itching wasreduced in 78% of the patients, and contact lens comfort was increasedin 71% of the patients. This shows that the vehicle itself is useful forsuch treatments.

In 76 to 94% of the GPC patients, loteprednol etabonate treatmentresulted in clinically meaningful improvement in the same areas. Theseresults are statistically significant (p<0.001) compared to theadministration of the vehicle alone. Thus, it is preferred toadministrate the vehicle containing the loteprednol etabonate foroptimum results.

We claim:
 1. A composition for ophthalmic or otolaryngological anti-inflammatory use comprising:(A) a corticosteroid in an amount of 0.01 to about 2% by weight and having a particle size of about 0.1 to 30 microns in diameter to substantially prevent discomfort upon use of the composition for said ophthalmic or otolaryngological anti-inflammatory treatment; (B) a nonionic polymer in an aqueous medium; (C) a nonionic tonicity agent in an amount sufficient to achieve isotonicity; and (D) a nonionic surface active agent in an amount sufficient to retain the corticosteroid, the nonionic tonicity agent and the nonionic polymer in a suspension.
 2. A composition for ophthalmic or otolaryngological anti-inflammatory use comprising:(A) a corticosteroid in an amount of about 0.01% to about 2% by weight, said corticosteroid having a particle size of about 0.1 to 30 microns diameter to substantially prevent discomfort upon use of the composition for said ophthalmic or otolaryngological anti-inflammatory applications; (B) a nonionic polymer in an aqueous medium; (C) a nonionic tonicity agent in an amount sufficient to achieve isotonicity; and (D) a nonionic surface active agent in an amount sufficient to retain the corticosteroid, the nonionic tonicity agent and the nonionic polymer in suspension, wherein the molar ratio of (A):(B):(D) is about 1:0.01:0.05 to about 1:20:1.
 3. The composition of claim 2 wherein the corticosteroid is selected from the group consisting of soft steroids having anti-inflammatory activity and is present in an amount of between about 0.01 and 1% by weight.
 4. The composition of claim 2 wherein the corticosteroid is loteprednol etabonate and is present in an amount of between about 0.05 and about 0.5% by weight.
 5. The composition of claim 2 wherein said nonionic polymer is a water soluble polymer selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, dextran and cyclodextrin.
 6. The composition of claim 2 wherein the nonionic polymer is present in an amount of about 0.2 to 2% by weight.
 7. The composition of claim 5, wherein said nonionic polymer is polyvinylpyrrolidone and is present in an amount of between about 0.3 to about 1.75% by weight.
 8. The composition of claim 2 wherein said nonionic surface active agent is tyloxapol and is present in an amount of about 0.05 to about 1% by weight.
 9. The composition of claim 2, wherein said nonionic surface active agent is a polyoxyethylene sorbitan mono-oleate ester.
 10. The composition of claim 7 wherein the nonionic tonicity agent is present in an amount of between about 1 to about 7% by weight.
 11. The composition of claim 10 wherein said non-ionic tonicity agent is a nonionic polyol and is present in an amount of between about 1.5 to about 4% by weight.
 12. The composition of claim 2 wherein said polyol is glycerol or mannitol.
 13. The composition of claim 2 further including a preservative for preventing microbial formation in said composition and is present in an amount of between about 0.0001 to about 0.025% by weight.
 14. The composition of claim 13 wherein said preservative is selected from the group consisting of benzalkonium chloride, disodium edetate and mixtures thereof.
 15. The composition of claim 2 further comprising an additional therapeutic drug in admixture with said corticosteroid, wherein said additional therapeutic drug is selected from the group consisting of betaxolol, atenolol, levobunolol, epinephrin, dipivalyl, oxonolol, acetazolamide-base, methazolamide, tobramycin, gentamycin, piroxicam, indomethacin, naproxen, phenylbutazone, ibuprofen, and diclofenac.
 16. The composition of claim 2 wherein the nonionic polymer is present in an amount of between about 0.2 to about 2% by weight; the nonionic tonicity agent is present in an amount of between about 1 to about 7% by weight; and the nonionic surface active agent is present in an amount of between about 0.05 to about 1% by weight.
 17. The composition of claim 16 further comprising a preservative for preventing microbial formation in said composition and is present in an amount of about 0.0001 to 0.025% by weight.
 18. A method for treating ophthalmic or otolaryngological inflammation which comprises applying to inflamed tissue a composition comprising:(A) a corticosteroid in an amount of 0.01 to about 2% by weight and having a particle size of about 0.1 to 30 microns in diameter to substantially prevent discomfort upon use of the composition for said ophthalmic or otolaryngological anti-inflammatory treatment; (B) a nonionic polymer in an aqueous medium; (C) a nonionic tonicity agent in an amount sufficient to achieve isotonicity; and (D) a nonionic surface active agent in an amount sufficient to retain the corticosteroid, the nonionic tonicity agent and the nonionic polymer in a suspension, wherein said composition is applied in an amount effective to treat said inflammation.
 19. The method of claim 18 wherein the nonionic polymer is present in an amount of between about 0.2 to about 2% by weight, the non-ionic tonicity agent is present in an amount of between about 1 to about 7% by weight, and the nonionic surface active agent is present in an amount of between about 0.05 to about 1% by weight, and wherein the molar ratio of (A):(B):(D) is about 1:0.01:0.05 to about 1:20:1.
 20. The composition of claim 2 wherein the corticosteroid has a mean particle size of ≦15 μm.
 21. The composition of claim 1 wherein the nonionic polymer is present in an amount of between about 0.2 to about 2% by weight, the non-ionic tonicity agent is present in an amount of between about 1 to about 7% by weight, and the nonionic surface active agent is present in an amount of between about 0.05 to about 1% by weight, and wherein the molar ratio of (A):(B):(D) is about 1:0.01:0.05 to about 1:20:1.
 22. The composition of claim 1 wherein said nonionic polymer is a water soluble polymer selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, dextran and cyclodextrin.
 23. The composition of claim 1 wherein the nonionic polymer is present in an amount of about 0.2 to 2% by weight.
 24. The composition of claim 1 wherein the nonionic tonicity agent is present in an amount of between about 1 to about 7% by weight.
 25. The composition of claim 1 wherein said nonionic tonicity agent is a nonionic polyol.
 26. The composition of claim 1 wherein said nonionic surface active agent is present in an amount of about 0.05 to about 1% by weight.
 27. The composition of claim 1, wherein said nonionic surface active agent is tyloxapol or a polyoxyethylene sorbitan mono-oleate ester.
 28. The composition of claim 1 including a preservative in an amount of between about 0.0001 and about 0.025% by weight for preventing microbial formation in said composition.
 29. The composition of claim 28 wherein said preservative is selected from the group consisting of benzalkonium chloride, disodium edetate and mixtures thereof.
 30. The method of claim 18 wherein the molar ratio of (A):(B):(D) is about 1:0.01:0.05 to about 1:20:1 when the corticosteroid is present. 